The present invention relates to methods for treating an antiviral treatment naive patient having chronic hepatitis C infection to eradicate detectable HCV-RNA involving a combination therapy using a therapeutically effective amount of a combination therapy of ribavirin and interferon-alpha for a time period of from 20 up to 50 weeks.
Chronic infection with hepatitis C virus is an insidious and slow-progressing disease having a significant impact on the quality of life. It can eventually result in cirrhosis of the liver, decompensated liver disease and/or hepatocelluar carcinoma.
Alpha interferon monotherapy is commonly used to treat chronic hepatitis C infection. However, this treatment is not always effective and sometimes results in intolerable side effects related to the dosage and duration of therapy. Ribavirin has been proposed as a monotherapy treatment for chronic hepatitis C infection (Thomas et al. AASLD Abstracts, Hepatology Vol. 20, NO. 4, Pt 2, Number 440, 1994). However, this monotherapy treatment has usually been found ineffective. Combination therapy of alpha interferon and ribavirin has been proposed: (Lai, et al. Symposium to the 9th Biennial Scientific Meeting Asian Pacific Association for the Study of the Liver. 1994); Combination treatment with interferon alpha-2b and ribavirin for chronic hepatitis C in patients who have failed to achieve sustained response to interferon alone: Swedish experience. J Hepatology, 1995;232 (Suppl 2):17-21. Brouwer J T, Nevens F, Michielsen P, et al.; What options are left when hepatitis C does not respond to interferon? Placebo-controlled Benelux multicenter retreatment trial on ribavirin monotherapy versus combination with interferon. J Hepatol. 1994;212 (Suppl 1):S17. Abstract WP2/08. Chemello L, Cavalletto L, Bernardinello E, et al. Response to ribavirin, to interferon and to a combination of both in patients with chronic hepatitis C and its relation to HCV genotypes. J Hepatol. 1994;212 (Suppl 1):S12. Abstract GS5/29; and The effect of interferon alpha and ribavirin combination therapy in naive patients with chronic hepatitis C, J. Hepatol. 1995;23(Suppl.2):8-12. Reichard et al. LANCET 1998; 351;83-87 disclosed that more chronic hepatitis C patients have a sustained virologic response with a combination of interferon alpha-2b and ribavirin for 24 weeks than with only interferon alpha-2b. Reichard et al. also disclosed that interferon-alpha-2b alone is sufficient to achieve a sustained response in such patients with HCV-RNA serum values above 3 million copies/mL. However, no one has described methods using alpha interferon and ribavirin which eradicate HCV-RNA in any long-term, effective manner for antivirally naive patients having a specific HCV genotype infection.
There is a definite need for a method for treating antiviral treatment naive patients having chronic hepatitis C infection with a combination of alpha interferon and ribavirin which eradicates HCV-RNA in any long-term, effective manner.
We have discovered that if the antiviral treatment naive patient has HCV genotype 1 infection, or if the antiviral treatment naive patient has an HCV genotype 1 infection, and a viral load of greater than 2 million copies per ml of HCV-RNA by quantitative PCR, then the administration of the combination therapy of alpha interferon and ribavirin is effected for a time period of 40-50 weeks, preferably 48 weeks.
We have also discovered that if the antiviral treatment naive patient has is HCV genotype 2 or 3 infection, then the administration of the combination therapy of alpha interferon and ribavirin is effected for a time period of 20-30 weeks, preferably 24 weeks.
The present invention provides a method of treating antiviral treatment naive patients having chronic hepatitis C infection to eradicate detectable HCV-RNA comprising administering a therapeutically effective amount of ribavirin and a therapeutically effective amount of interferon-alpha for a time period of at least 20 up to 50 weeks, wherein when the antiviral treatment naive patient has a HCV genotype 1 infection, the time period of administring is about 40 to 50 weeks or wherein when the antiviral treatment naive patient has a HCV genotype 2 or 3 infection, the time period of administering is about 20 to 30 weeks.
The present invention also provides a method of treating antiviral treatment naive patients having chronic hepatitis C infection and HCV genotype 1 to eradicate detectable HCV-RNA comprising administering a therapeutically effective amount of ribavirin and a therapeutically effective amount of interferon-alpha for a time period of at least 40 to 50 weeks, such that about 17% of the patients having no detectable HCV-RNA at the end of said 20 to 30 week time period also have no detectable HCV-RNA for at least 24 weeks after the end of said administration, and such that about 29% of the patients having no detectable HCV-RNA at the end of said 40-50 week time period also have no detectable HCV-RNA for at least 24 weeks after the end of said administration.
In another embodiment, the present invention relates to a method of treating antiviral treatment naive patients having chronic hepatitis C infection and having HCV genotype 1, 4, 5 or 6 to eradicate detectable HCV-RNA comprising administering a therapeutically effective amount of ribavirin and a therapeutically effective amount of interferon-alpha for a time period of at least 40 to 50 weeks, such that about 29% of the HCV genotype 1 patients and about 39% of the HCV genotype 4, 5 or 6 patients having no detectable HCV-RNA at the end of said time period also have no detectable HCV-RNA for at least 24 weeks after the end of said administration.
Another embodiment of the invention relates to a method of treating antiviral treatment naive patients having chronic hepatitis C infection comprising administering a therapeutically effective amount of ribavirin and a therapeutically effective amount of interferon-alpha for a time period of 20 up to 50 weeks, such that about 41% of the patients having no detectable HCV-RNA at the end of said 40 to 50 week time period also have no detectable HCV-RNA for at least 24 weeks after the end of said administration; wherein the patients who have no detectable HCV-RNA at the end of a 20 to 30 week time period of said 20 to 50 week time period and also are known to be HCV-genotype 2 or 3 are treated for only 20 to 30 weeks of said 40 to 50 week period.
One aspect of the invention involves a method of treating antiviral treatment naive patients having chronic hepatitis C infection and having HCV genotype type 2 or 3 comprising administering a therapeutically effective amount of ribavirin and a therapeutically effective amount of interferon-alpha for a time period of about 20 to 30 weeks, such that about 64-65% of the patients having no detectable HCV-RNA at the end of said time period also have no detectable HCV-RNA for at least 24 weeks after the end of said administration.
Another aspect of the invention relates to a method of treating antiviral treatment naive patients having chronic hepatitis C infection and having HCV genotype type 1 and having a viral load of less than or equal to 2 million copies as measured by HCV-RNA/qPCR to eradicate detectable HCV-RNA comprising administering a therapeutically effective amount of ribavirin and a therapeutically effective amount of interferon-alpha for a time period of at least 40 to 50 weeks, such that about 33% of the patients having no detectable HCV-RNA at the end of said time period also have no detectable HCV-RNA for at least 24 weeks after the end of said administration.
Yet another aspect of the invention involves a method of treating antiviral treatment naive patients having chronic hepatitis C infection and having HCV genotype type 1 and having a viral load of greater than 2 million copies as measured by HCV-RNA/qPCR to eradicate detectable HCV-RNA comprising administering a therapeutically effective amount of ribavirin and a therapeutically effective amount of interferon-alpha for a time period of at least 40 to 50 weeks, such that about 27% of the patients having no detectable HCV-RNA at the end of said time period also have no detectable HCV-RNA for at least 24 weeks after the end of said administration.
The interferon-alpha administered is preferably selected from interferon alpha-2a, interferon alpha-2b, a consensus interferon, a purified interferon alpha product or a pegylated interferon-alpha, including a pegylated interferon-alpha-2a or a pegylated interferon alpha-2b.
More preferably, the interferon-alpha is selected from interferon alpha-2a, interferon alpha-2b, or a purified interferon alpha product and the amount of interferon-alpha administered is from 2 to 10 million IU per week on a weekly, TIW, QOD or daily basis. In a preferred embodiment, the interferon-alpha administered is interferon-alpha-2b and the amount of interferon-alpha is administered 3 million IU TIW.
Alternatively, the interferon-alpha administered is consensus interferon and the amount of interferon-alpha administered is from 1 to 20 micrograms per week on a weekly, TIW, QOD or daily basis. In another embodiment, the interferon-alpha administered is a pegylated interferon alpha-2b and the amount of interferon-alpha administered is from 0.5 to 2.0 micrograms/kilogram per week on a weekly, TIW, QOD or daily basis. Alternatively, the interferon-alpha administered is a pegylated interferon alpha-2a and the amount of interferon-alpha administered is from 20 to 250 micrograms/kilogram per week on a weekly, TIW, QOD or daily basis. The use of interferon alpha-2a or pegylated interferon alpha-2a or interferon alpha-2b or pegylated interferon alpha-2b is preferred.
During the 20-30 week and during the 40-50 week time periods, the amount of ribavirin administered is 800 to 1200 mg per day, preferably 800, 1000 or 1200 mg per day, and the amount of interferon alpha-2a or interferon alpha-2b administered is from 2 to 10 million IU per week on a weekly, TIW, QOD or daily basis, more preferably 3 million IU TIW.